Various dermally absorbable type preparations containing tulobuterol have been recently proposed as preparations making up the demerits of the oral preparation containing tulobuterol (See Japanese Patent Publication A 11-228395, Japanese Patent No. 2753800 (Japanese Patent Publication A 7-285854), WO 97/14411 and Japanese Patent No. 2633089 (Japanese Patent Publication A 5-194202)).
A patch prepared by dissolving tulobuterol into an adhesive has such a demerit as the duration necessary to sustain its effective serum concentration is not attained.
Therefore, techniques to increase the concentration of tulobuterol or to contain much amount of it by thickening an adhesive layer have been tried.
For example, in Japanese Patent Publication A 11-228395, a tulobuterol-patch which has a structure to fully dissolve tulobuterol is proposed. However, when such a patch is preserved for a long time due to the high concentration of tulobuterol, the preparation is apt to receive the influence by changes of circumstances such as temperature, etc. For example, even if the preparation has a good quality just after preparing it, with the passage of time there is a possibility that drug-release pattern becomes different from one at the earlier time because tulobuterol crystallizes in the adhesive layer or changes of the concentration occurs.
In general essential physical properties such as adhesivity and shape retention of a patch are broken down and it is impossible to stably release the drug when a large amount of ingredients, which are either essential or unessential, are contained in the patch.
In regard to a patch containing much amount of tulobuterol, when the amount of an adhesive is too much, the essential physical properties become worse and during application of the patch, it gives an uncomfortable feeling to a patient and there is also a possibility to drop it out due to rubbing with clothes.
Further, in regard to a patch in which tulobuterol is much dissolved in the higher concentration, it can not help containing much amount of tulobuterol and therefore, it is neither economical nor practical.
On the other hand, a patch in which both soluble type tulobuterol and crystalline type tulobuterol are contained in the specific rates (see Japanese Patent No. 2753800), a patch prepared by recrystallizing tulobuterol in an adhesive (see WO97/14411), a patch consisting of tulobuterol and a specific co-polymer, wherein tulobuterol is suspended or microcapsulized and they are included in the adhesive layer, or a patch prepared by constructing matrix layers, adhesive layers or reservoir layers, and by laminating theses layers (see Japanese Patent No. 2633089), etc., were proposed as a dermally absorbable type patch which is aimed for a long lasting preparation of tulobuterol.
However, in regard to these patches, when they are preserved for long time, they are apt to receive the influence by changes of circumstances such as temperature, etc. For example, owing to the temperature rising in summer, tulobuterol in crystals, suspensions or microcapsules contained in the patch dissolves and on the contrary, owing to the temperature dropping in winter, the dissolved tulobuterol begins to crystallize. Also in case of laminated type preparations, owing to changes of circumstances, movement (transfer) of ingredients such as tulobuterol and other ingredients occurs between matrix laminated layers and reservoir-layers, and the release pattern of tulobuterol from the patch is changed and there is a possibility to give the influence to the therapeutic effect of tulobuterol.
As well, these patches require complex techniques for suspending tulobuterol, microcupsulation of it and stable blending it into the matrix, and selection of the condition for recrystallization of it in the matrix, construction of the matrix and the reservoir layer, laminating, etc. They are problematic.